usp efforts on the storage and distribution of drug products:...

USP Efforts on the Storage and Distribution of Drug Products: Historical Background, General Chapters and What Next?Desmond G. Hunt, Ph.D.Principal Scientific Liaison

APEC-LSIF USP Center of Excellence for Global Supply Chain Integrity (Webinar)January 27, 2021

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Resolution No. 10 – Drug Storage Standards

At the 1995 Quinquennial meeting, USP adopted Resolution 10, which encouraged USP to identify compendial items for which storage and shipment in the distribution system are of special concern, so that proper storage and shipment instructions can be included with the compendial item, such that the integrity of the item is maintained until received by the patient.

Suppliers

Manufacturers

Wholesale/Distributors

Pharmacies/Hospitals

Healthcare Providers

PatientsGOOD DISTRIBUTION PRACTICES

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Topic Development

Initial step in addressing this resolution was to conduct a survey. • Goal of the survey

Determine if there were temperature-sensitive products in the market and if so, how many.

• Based on the poor response from the survey, shipping studies were conducted to determine what is the temperature and humidity to which drugs are exposed to during shipping.

• Shipping studies were conducted Temperature Fluctuations During Mail Order Shipment of Pharmaceutical Articles Using Mean Kinetic Temperature Approach, PF 23 (3), 1997

Temperature and Humidity Conditions During Shipment in International Commerce PF 25 (2), 1999

A Study of the Temperature and Humidity Variations in the Shipment and Distribution of Anthrax Vaccines PF 26 (3), 2000

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<1141> Packaging, Storage, and Distribution of Pharmacopeial Articles

Initial chapter developed on the topic in 2000:• Objective: outline concerns around the proper

packaging, storage and distribution of temperature-sensitive drug products. Packaging

Storage

Distribution

Special Packaging Considerations

Environmental Issues

Labeling

• Based on industry feedback it was decided to expand the topic to include to all drug products, not just temperature-sensitive preparation.

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<1079> Good Storage and Shipping Practices

Chapter development/official 2000-2005:• Storage in Warehouses, Pharmacies, Trucks, Shipping Docks and Other

Locations• Distribution and Shipment of Pharmacopeial Articles• Shipment from Manufacturer to Wholesaler• Shipment from Manufacturer or Wholesaler to Pharmacy• Shipment from Pharmacy to Patient or Customer• Returns of Pharmaceutical Articles from Patient or Customers• Storage of Physician Samples Handled by Sale Representatives in Automobiles• Stability, Storage, and Labeling• Statement/Labeling of Immediate Containers or Package Insert

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<1079> Good Storage and Shipping Practices

Chapter update in 2007: Responsibilities of Supply Chain

Partners Labeling Information Quality Management System

• Good Documentation Practices

• Storage Management System

• Distribution Management System

• Environmental Management System

• Risk Management System

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What did we learn? USP’s current approach to GDP has been

piecemeal:• Individual components, (e.g. Excipients; Drug

Products)• Individual topics (e.g. Storage & Shipping; Supply

Chain Integrity, Importation and Exportation) A holistic approach to Good Distribution Practices

(GDP) is preferred: • Acquisition of ingredients (API’s, excipients)• Authentication and drug pedigree steps• Delivery of medicines to the end-users• Adherence to labeled storage conditions

USP Supply Chain Workshop 2012

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<1083> Good Distribution Practices

Four GDP topics covering quality management system, environmental conditions management, importation and exportation management and supply chain integrity and security will serve as the foundation for the GDP chapters.

Generally, they apply to all materials and products, regardless of their regulatory category.

These topics include the basic principles that provide guidance on how to establish and maintain:• a quality management system that ensures the quality, integrity, safety and efficacy of materials and

products during sourcing and distribution (e.g. personnel, storage buildings, transportation vehicles, etc.).

• temperature and humidity control during product holding and transportation. • supply chain integrity from importation and exportation procedures to minimizing counterfeiting, cargo

thefts, diversion • traceability of individual products and shipments throughout the supply chain.

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<1083> Good Distribution Practices

Pharmacopeial Forum: 38 (2) March 2012

The Drug Quality and Security Act (DQSA), was enacted by US Congress on November 27, 2013.

Reevaluation of the <1083> suite of chapters, in light of the new legislation, led to postponement• Renewed focus on the topic of storage and shipping of finished drug products

GOOD DISTRIBUTION PRACTICES

(GDP)

QUALITY MANAGEMENT

SYSTEM

ENVIRONMENTAL CONDITIONS

MANAGEMENT

IMPORTATION & EXPORTATIONMANAGEMENT

SUPPLY CHAIN INTEGRITY &

SECURITY

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Recent Development and Revision

Storage and Transportation <1079> Risks and Mitigation Strategies for the Storage and Transportation of

Finished Drug Products (2020)

<1079.1>Storage and Transportation of Investigational Drug Products (2018)

Temperature Control <659> Packaging and Storage Requirements (2020)

<1079.2 > Mean Kinetic Temperature in the Evaluation of Temperature Excursions During Storage and Transportation of Drug Products (2020)

<1079> Risks and Mitigation Strategies for the Storage and Transportation of Finish Drug Products – Game-Changer Rationale

Glaucia Karime Braga, PhDQuality Auditor, FURP; Professor, UNIP University; USP Expert Committee Member


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Pharmaceutical Supply Chain Overview

Complexity of the supply chain

Key activities: Storage and transportation

Different modes of transport and climate zones

Shared responsibility

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Goal within the Pharmaceutical Supply Chain

To maintain the integrity of drug productsthroughout the supply chain

To ensure drug products reach the enduser with their safety, identity, strength,quality, and purity intact

Provide evidence that drug products arestored and shipped according to labeledstorage conditions

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USP General Chapter Rationale

Previous: <1079> Good Storage and Distribution Practices for Drug Products

Good practices approach

Potentially overlaps regulatory perspective

Current: <1079> Risks and Mitigation Strategies for Storage and Transportation of Finished Drug Products

Risk-based approach

Provides education and builds knowledge

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Harmonized Reference in Quality Risk Management –ICH Q9

Key points for <1079>

FAQ in Quality Risk Management1. What might go wrong? 2. What is the likelihood? (Probability)3. Which are the consequences?

(Severity)4. Can we detect? (Detectability) 5. How can we mitigate?

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New <1079> and Risk-Based Approach

Risk identification is the systematic use of information to identify potential sources of harm (hazards). Information can include historical data, theoretical analysis, informed opinions, product and process knowledge, and the concerns of stakeholders. Risk identification addresses the question:

What might go wrong?

Mitigation strategies are a part of the risk control process, specifically risk reduction. Risk reduction addresses the question:

What can be done to reduce or eliminate risks?

In this way, risk reduction can include actions taken to mitigate the severity or probability of harm or loss. Processes that improve the detectability of hazards and quality risks can also be used as part of a risk control strategy.

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Risk-based approach for a QMSProduct knowledge includes but is not limited to the following: Intended use

Storage conditions

Potential hazards to environment and personnel (e.g., hormones, cytotoxic drug products, radiopharmaceuticals)

Inherent vulnerability (e.g., high potential for abuse, high-value drugs attractiveness cargo theft, counterfeiting, and diversion)

Process knowledge includes, but is not limited to, the following: Knowledge of supply chain partners

Physical modes of transportation (air, sea, rail, or road)

Transportation routes

National and international regulation

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Quality Management System

Documentation Training ResourcesInstructions,

Schedules and Records

INFORMATION

Competence,Development and Understanding of

Instructions

COMPREHENSION

Infrastructure, Personnel and Organization

CAPABILITY

Qualification/ValidationEnsure suitability of the

purpose Warehouse/packaging

system/transportation and ERP

ASSURANCE

Risk-based approach for a QMS

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Storage and Transport Main Risks and Mitigation Strategies

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Applicable Mitigation Strategies

Role of the Organization within the Supply Chain Manufacturer Wholesaler

distributor Pharmacy/ Compounding Pharmacy

Hospital/Health care providers

Brokers Freight Forwarders

Documentation (Manuals, Procedures, Protocols, Records) Quality Manual Yes Yes Yes Yes Yes Yes Labeling Yes Yes Yes Yes No No Procurement Yes Yes Yes Yes Yes Yes Receiving Yes Yes Yes Yes No Yes Picking Yes Yes Yes Yes No Yes Packing Yes Yes Yes No No No Sales Yes Yes Yes No Yes No Storage Yes Yes Yes Yes No Yes Transportation Yes Yes Yes No1 No Yes Supplier Qualification Yes Yes Yes Yes Yes Yes Customer Qualification Yes Yes No No Yes Yes Quality Agreements Yes Yes Yes Yes Yes Yes Licenses and Authorizations Yes Yes Yes Yes Yes Yes Recall Yes Yes Yes Yes Yes Yes Return Yes Yes Yes Yes No No Temporary parking No No No No No Yes Excursion handling Yes Yes Yes Yes No Yes Disposal of expired and rejected drug product Yes Yes Yes Yes No Yes Pest Control and Pallet Conservation Yes Yes Yes Yes No Yes Training Yes Yes Yes Yes Yes Yes Resources Product segregation Yes Yes Yes Yes No Yes Storage area (layout/logical flow) Yes Yes Yes Yes No Yes2

Maintenance Yes Yes Yes Yes No Yes Calibration Yes Yes Yes Yes No Yes Monitoring Systems and Alarms Yes Yes Yes Yes No Yes Appropriate number of personnel Yes Yes Yes Yes Yes Yes Organizational chart/job descriptions Yes Yes Yes Yes Yes Yes Qualification/Validation Temperature Mapping Yes Yes Yes Yes No Yes Shipping Packaging qualification Yes Yes Yes No1 No No Software validation (automated checking systems, ERPs, ERP-like systems)

Yes Yes Yes Yes Yes Yes

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<1079> Summary

The principles can be used globally and are useful for API,dietary supplements,

Is not meant to prescribe specific approaches or discussregulatory frameworks

Was written to provide helpful information to stakeholders ofthe Pharmaceutical Supply Chain

The New <1079.2> Mean Kinetic Temperature in the Evaluation of Temperature Excursions During Storage and Transportation of Drug ProductsChris AndersonQuality Director – Cardinal Health and USP Expert Committee Member


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<1079> Risk Mitigation Strategies for the Storage of Finished Drug Products

Primary chapter used for the storage, handling, and distribution of drugs – references <659>, <1079.2> and to articles on MKT

<1079> 4.1.5 EXCURSION HANDLING• Short-term temperature excursions can occur during distribution, storage, and

transportation….• See <659> for excursion allowances and MKT limits and Mean Kinetic Temperature in

the Evaluation of Temperature Excursions During Storage and Transportation of Drug Products <1079.2> for MKT. MKT should be calculated for the period of time that a drug is in residence at a warehouse and/or in transit on a truck to avoid the problem of diluting the impact of excursions by calculating annual MKT values. 1,2 (<1079> December 1, 2020, p.12)

1 Seevers RH, Hofer J, Harber P, Ulrich DA, Bishara R. The use of mean kinetic temperature (MKT) in the handling, storage and distribution of temperature sensitive pharmaceuticals. Pharmaceutical Outsourcing. May/June 2009;12–17.2 Anderson C, Seevers R, Hunt D. The use of mean kinetic temperature to aid evaluation of temperature excursions: proper and improper application. Pharm Forum. 2018;44(4)

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<659> Controlled Cold Temperature (CCT)

Maintained thermostatically between 2º and 8ºC Excursion not to exceed 24 hours Excursions between 2º to15ºC (storage and transportation) are permitted as long as

the MKT does not exceed 8ºC) Excursions cannot occur more than one time during possession of the product within

the supply chain, unless directed by the manufacturer or supported by stability data Calculation and documentation of MKT:

• References <1079.2> Mean Kinetic Temperature in the Evaluation of Temperature Excursion During Storage and Transportation of Drug Products

• References Anderson C, Seevers R, Hunt D The Use of Mean Kinetic Temperature to Aid Evaluation of Temperature Excursions: Proper and Improper Application. Pharm Forum. 2018; 44(4) http://www.usppf.com/pf/pub/index.html

http://www.usppf.com/pf/pub/index.html

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<659> Controlled Room Temperature (CRT)

Maintained thermostatically between 20º and 25ºC Excursions cannot exceed 24 hours Excursions between 15-30ºC (…pharmacies, hospitals, and warehouses, and during shipping allowed as

long as the MKT does not exceed 25ºC) Transient spikes up to 40ºC are permitted as long as:

• They do not exceed 24 hours• MKT cannot exceed 25ºC

CRT alternatively can be stored and shipped Cool or CCT unless otherwise specified on the monograph or on the label

Storage time in controlled cold or cool place cannot be used to calculate excursion temperature outside of controlled room temperature ranges

Spikes above 40ºC may be permitted only if the manufacturer so instructs Calculation and documentation of MKT:

• References <1079.2> Mean Kinetic Temperature in the Evaluation of Temperature Excursion During Storage and Transportation of Drug Products

• References Anderson C, Seevers R, Hunt D The Use of Mean Kinetic Temperature to Aid Evaluation of Temperature Excursions: Proper and Improper Application. Pharm Forum. 2018; 44(4) http://www.usppf.com/pf/pub/index.html

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<1079.2> Mean Kinetic Temperature in the Evaluation of Temperature Excursions during Storage and Transportation of Drug Products

Math Calculations*• Controlled Room Temperature (CRT) – Use 30 days (or average time product is in your possession) of

temperature data

• Controlled Cold Temperature (CCT) – Use 24 hours of temperature data

• Temperature data for calculations should go back from the end of the excursion (e.g., if a CCT excursion began on June 5th, 2020 at 7:30 AM and ended at 10:30 AM on the same day you would calculate the MKT using temperature data from June 4th, 2020 at 10:30 AM through June 5th, 2020 at 10:30 AM)

• Temperature data points for CRT, USP recommends to use the high and the low temperature for each day

• Temperature data points for CCT, USP recommends to use all the data points recorded during the time period (e.g., every 15 minutes)

*This in the process of being changed to move MKT calculation to <1160> Pharmaceutical Calculations

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Mean Kinetic Temperature Stimuli Articles

The Use of Mean Kinetic Temperature to Aid Evaluation of Temperature Excursions: Proper and Improper Applications, published in the PF 44(4), July 2018:• Stimuli Article to the revision of <659> and <1079>

−Authors: Chris Anderson, Desmond Hunt, and Robert Seevers published July of 2018• Covered the use of MKT for excursions for CRT and CCT products

The Use of Mean Kinetic Temperature to Aid Evaluation of Temperature Excursions for Controlled Cold Temperature Drugs: Proper and Improper Application PF 45(5), September 3, 2019• New Stimuli Article to the revision of <659> and <1079.2>, the new MKT excursion

management chapter−Authors: Chris Anderson, Desmond Hunt, and Robert Seevers published September of

2019• Greater focus on CCT (2-8ºC) excursions

30© 2019 USP

The MKT Equation

ΔH = 83.144 kJ/mol

R = 8.3144 × 10-3 kJ/mol · K (universal gas constant)

T1 = Value for the temperature recorded during the first time period; the time periods can be minutes, hours, days, or weeks

Tn = Value for the temperature recorded during the nth time period

n = Total number of storage temperatures recorded during the observation period

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CRT 52-Week MKT Versus 30-Day Example

52-Week MKT = 23.98°C

aMKT calculated for 30 days is 28.98°C (84.16°F), which is over 25°C (77°F), and is unacceptable.bDay within the 365-day study period.

Temperature (°C) Temperature (°C) Temperature (°C)Dayb High Low Day High Low Day High Low158 24.37 19.58 168 24.19 19.79 178 30.91 23.65159 22.28 19.56 169 23.69 19.67 179 29.71 22.98160 23 19.85 170 32.4 25.44 180 29.44 22.84161 23.5 19.58 171 32.72 26.01 181 28.49 22.84162 23.43 18.93 172 31.04 24.61 182 28.64 21.83163 22 19.34 173 30.52 23.58 183 30.17 22.06164 22.43 19.54 174 29.6 23.92 185 29.99 23.58165 22.92 19.56 175 30.98 24.19 186 31.44 24.21166 23.94 19.34 176 32.27 25.91 187 32 24.83167 24.92 19.83 177 32.2 27.23 188 33.58 26.6

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CRT 52-Week MKT Versus 30-Day Example

52-Week MKT = 22.75 °C

Temperature (°C) Temperature (°C) Temperature (°C)Dayb

High Low Day High Low Day High Low64 23.33 21.67 74 22.78 22.22 84 23.33 22.7865 23.89 21.67 75 22.77 22.22 85 23.33 22.7866 23.33 22.78 76 23.33 22.22 86 23.33 22.7867 24.44 23.33 77 23.33 22.22 87 23.89 22.78

68 23.89 23.33 78 23.33 22.22 88 23.89 23.3369 23.33 22.78 79 23.89 22.78 89 25 22.7870 22.78 22.22 80 24.44 22.78 90 23.33 22.7871 23.33 22.22 81 23.89 22.22 91 22.78 22.7872 23.89 22.22 82 23.89 22.22 92 24.44 22.7873 22.78 22.22 83 23.33 22.22 93 25.56 23.33

aMKT calculated for 30 days was 23.14°C (73.65°F), which was under 25°C (77°F) and therefore acceptable. bDay within the 365-day study period.

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CCT MKT Example

Passive Shipper Example

In this example, a passive shipper went out of CCT at 16 hours and 45 minutes1. The high temperature was 15°C2. The excursion was less than 24 hours 3. The MKT was 10.5°C for the last 24 hours (outside the excursion MKT limit)4. In this case, the product should be quarantined and the manufacturer(s) should be contacted for

disposition

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CCT MKT Example

Passive Shipper Example

In this example, a passive shipper went out of CCT at 23 hours and 30 minutes1. The high temperature was 14.5°C2. The excursion was less than 24 hours 3. The MKT was 6.5°C for the last 24 hours (outside the excursion MKT limit)4. In this case, the product would be considered acceptable for release to salable inventory

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CCT MKT Example

Refrigerated Trailer Example

In this example, a refrigerated trailer making a delivery went out of CCT at 51 hours1. The high temperature was 13.1°C2. The excursion was less than 24 hours 3. The MKT was 10.88°C for the last 24 hours (outside the excursion MKT limit)4. In this case, the product should be quarantined and the manufacturer(s) should be contacted

for disposition

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CCT MKT Example


In this example, a refrigerated trailer making a delivery went out of CCT range at 62 hours and 45 minutes1. The high temperature was 10.95°C2. The excursion was less than 24 hours 3. The MKT was 7.28°C for the last 24 hours (within the excursion MKT limit)4. In this case, the product would be considered acceptable to release to salable inventory

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CCT MKT Example


In this example, a refrigerated trailer making a delivery went out of CCT range multiple times due to a cycle-type of active system that turns the unit off until a target temperature is reached triggering the unit to come back on until a set point towards the lower end of the range is reached1. The high temperature was 10.1°C but the low temperature was -2.2°C 2. The excursions were each less than 24 hours, 21 hours and 45 minutes between the first and last excursion 3. The MKT was 6°C for 24 hours (within the excursion MKT limit)4. In this case, however, the system is out of control and the USP would recommend evaluation by the product

manufacturers

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COVID-19 Vaccine “Frozen”

For the upcoming COVID-19 Frozen vaccinations (-20° and -70°C), USP does not currently recommend an excursion range outside of what has been published by the manufacturers. Additionally, USP does not currently recommend using MKT to evaluate any excursions of frozen COVID-19 Vaccines.

USP will be posting operational guidance for healthcare professionals aimed at handling and administration.

39© 2019 USP

What is Next?

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1. <1079.3> Monitoring Devices—Time, Temperature, and Humidity (Current ⟨1118⟩)

2. < 1079.4> Qualification of Storage Areas

3. <1079.5> Qualification of Shipping Systems

4. <1079.6> Transport Route Profiling Qualification

5. <1079.7> Information Systems for Distribution Validation/Verification Studies

usp efforts on the storage and distribution of drug products:...

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